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BACKGROUND: Sugammadex is a relatively new molecule that reverses neuromuscular block induced by rocuronium. The particular structure of sugammadex traps the cyclopentanoperhydrophenanthrene ring of rocuronium in its hydrophobic cavity. Dexamethasone shares the same steroidal structure with rocuronium. Studies in vitro have demonstrated that dexamethasone interacts with sugammadex, reducing its efficacy. In this study, we investigated the clinical relevance of this interaction and its influence on neuromuscular reversal.

METHODS: In this retrospective case-control study, we analyzed data from 45 patients divided into 3 groups: dexamethasone after induction group (15 patients) treated with 8 mg dexamethasone as an antiemetic drug shortly after induction of anesthesia; dexamethasone before reversal group (15 patients) treated with dexamethasone just before sugammadex injection; and control group (15 patients) treated with 8 mg ondansetron. All groups received 0.6 mg/kg rocuronium at induction, 0.15 mg/kg rocuronium at train-of-four ratio (TOF) 2 for neuromuscular relaxation, and 2 mg/kg sugammadex for reversal at the end of the procedure at TOF2. Neuromuscular relaxation was monitored with a TOF-Watch® system.

RESULTS: The control group had a recovery time of 154 ± 54 seconds (mean ± SD), the dexamethasone after induction group 134 ± 55 seconds, and the dexamethasone before reversal group 131 ± 68 seconds. The differences among groups were not statistically significant (P = 0.5141).

CONCLUSIONS: Our results show that the use of dexamethasone as an antiemetic drug for the prevention of postoperative nausea and vomiting does not interfere with reversal of neuromuscular blockade with sugammadex in patients undergoing elective surgery with general anesthesia in contrast to in vitro studies that support this hypothesis.

Sugammadex, a modified γ-cyclodextrin, is a relatively new molecule that specifically reverses neuromuscular block induced by steroidal drugs, such as rocuronium and vecuronium.1 Its particular ring-shaped structure describes a central hydrophobic cavity in which rocuronium and vecuronium can be encapsulated.2,3 The cyclopentanoperhydrophenanthrene structure, typical of steroidal compounds, has the right dimension to enter the sugammadex cavity. This is the reason why larger drug muscle relaxants such as cisatracurium are not encapsulated by sugammadex. Other appropriately sized molecules of clinical significance also may be bound by sugammadex. Zwiers et al.4 studied possible in vitro interactions between sugammadex and 300 molecules. They found that only 3 compounds showed an affinity for the cyclodextrin strong enough to displace rocuronium and vecuronium from the sugammadex cavity: toremifene, fusidic acid, and flucloxacillin. They also reported that rocuronium has a 10,000-fold greater affinity than dexamethasone for sugammadex binding.

By contrast, a 2014 article has raised concerns about the possible antagonism of sugammadex reversal of rocuronium or vecuronium by corticosteroids. Rezonja et al.5 demonstrated that dexamethasone inhibits sugammadex neuromuscular reversal activity in vitro in innervated primary human muscle cells. These authors concluded that sugammadex’s efficacy for reversal of rocuronium-induced neuromuscular block may be diminished by dexamethasone and emphasized the need for further investigation to determine the clinical relevance of these findings.

Dexamethasone is one of the most widely used corticosteroids for treating many clinical conditions, such as laryngeal, cerebral, and surgical edema,6 as well as in combination with multimodal analgesia,7,8 and for the prevention of postoperative nausea and vomiting (PONV). It shares with rocuronium the same cyclopentanoperhydro-phenanthrene structure and very similar molecular dimensions. These characteristics could be a determinant for a possible antagonistic interaction of dexamethasone toward rocuronium for sugammadex binding (Fig. 1). No clinical studies have explored the possible clinical impact of the in vitro dexamethasone-sugammadex interaction described by Rezonja et al.5 in humans.

The aim of this study was to explore whether the interaction of dexamethasone with sugammadex would have a clinical impact for reversal of neuromuscular blockade in patients undergoing general anesthesia. Given the substantial differences in affinities of rocuronium and dexamethasone for sugammadex, we hypothesized that administration of dexamethasone would not impair sugammadex’s reversal of rocuronium.

METHODS

The study was approved by the IRB of Federico II University of Naples, Naples, Italy (protocol number 185/15/ESPROSP), and was conducted in compliance with the Declaration of Helsinki (1964 and following amendments), current Good Clinical Practices, and the applicable European and local regulatory requirements.

Patients in our university hospital usually are invited to freely give written informed consent to authorize the use of their clinical data for research purposes. All subjects included in this study provided consent for the use of their data. Given the retrospective nature of the study, registration was not applicable.

Subjects

This was a retrospective, case-control study conducted at Federico II University Hospital of male and female patients undergoing general anesthesia for colon surgery, abdominal wall surgery, thyroidectomy, breast surgery, cholecystectomy, oral surgery, and maxillofacial surgery. Inclusion criteria were age 18 to 65 years, body mass index between 18 and 30 kg/m2, ASA physical status I or II, and 2 or more risk factors for PONV according to the Apfel score9: female sex, history of PONV or motion sickness, nonsmoking status, and intra- or postoperative use of opioids. Exclusion criteria included a history of sensitivity or idiosyncrasy to chemically related compounds or excipients that may be used in the study or to any other drug; previous exposure to sugammadex within 3 months before the start of treatment; pregnancy; family history of malignant hyperthermia; use of steroidal compounds; therapy with fusidic acid, toremifene, or flucloxacillin; clinically relevant history or presence of any medical disorder that could potentially interfere with the trial such as neuromuscular diseases; diabetes; inability to understand the nature and extent of the study and the procedures required; QTc interval prolongation; moderate/severe renal or hepatic dysfunction; and use of anticoagulant drugs or coagulation disorders.

We analyzed 813 medical records of patients undergoing surgery from May 2014 to November 2014. Five hundred six medical records were excluded because they did not meet inclusion criteria; 257 were excluded because they did not report the timing of ondansetron and dexamethasone administration. Seventeen medical records reported administration of ondansetron just after anesthetic induction, 15 reported administration of dexamethasone just before reversal, and 18 reported administration of dexamethasone just after induction. We decided to analyze 15 medical records per group on the basis of our statistical analysis (see the section “Sample Size”), selecting them from each group according to a chronological criterion.

Neuromuscular Monitoring

A TOF-Watch-SX® acceleromyograph (Organon Ltd., Dublin, Ireland) was used for neuromuscular monitoring. Electrodes were attached on the ulnar nerve proximal to the wrist, and the piezoelectric probe was placed at the tip of the thumb with a hand adapter. The forearm was fixed in the same position throughout the entire procedure, from the time of calibration to neuromuscular reversal. Skin temperature was continuously monitored. Train-of-four (TOF) data were not used for skin temperature <32°C. Automatic calibration (CAL-2 mode) was performed after induction: this function of TOF-Watch-SX automatically determines the supramaximal current and the control twitch height, thus simultaneously calibrating the device. A current of 60 mA was used initially, and the T1 response set to 100% after a few single twitches. The stimulation current was then decreased gradually in increments of 5 mA and the response registered until it decreased <90% of the baseline value. Current intensity just before the decrease of the T1 response <90% of the reference value was used as the maximal current. The supramaximal current is defined as a current that exceeds the maximal current of 10%: this supramaximal current is used for stimulation, and the response is finally set to 100%. The TOF stimulation response was registered every 15 seconds after rocuronium induction.

Intervention

All patients fasted for at least 8 hours before surgery. Anesthesia was induced with 1.5 to 2.5 mg/kg propofol and 1 to 2 μg/kg fentanyl. After acceleromyograph calibration, a single dose of 0.6 mg/kg rocuronium was administered, and tracheal intubation was performed. Within 10 minutes after induction, the control group received 8 mg ondansetron as antiemetic prophylaxis, whereas the dexamethasone after induction group received 8 mg dexamethasone as antiemetic prophylaxis. Within 5 minutes before sugammadex administration, the dexamethasone before reversal group received 8 mg dexamethasone. Additional doses of 0.15 mg/kg rocuronium were administered during surgery at TOF2 if required. Anesthesia was maintained by sevoflurane and remifentanil and titrated according to hemodynamic and autonomic responses. At the end of surgery, sevoflurane was decreased to an end-tidal concentration of 0.8% to 1%, and 2 mg/kg sugammadex was administered when the acceleromyograph registered a TOF2 response.

We selected medical records to have 2 different case groups with different timings of dexamethasone administration: just after induction of anesthesia and just before sugammadex administration. We did this to investigate the possible chemical interaction between dexamethasone and sugammadex at different dexamethasone plasma concentrations. We assumed that in the group in which dexamethasone was administered shortly before sugammadex, dexamethasone concentrations would be near maximal serum concentrations. Reversal time to a TOF ratio >0.9 was recorded.

Sample Size

We assumed that in the control group, the time required to reverse a moderate rocuronium-induced block with 2 mg/kg sugammadex from TOF2 to TOF ratio 0.9 was on average 2 minutes (SD, 0.7).10,11 To detect a 50% increase in the time required to reverse moderate blockade, assuming a similar SD, with an α error of 0.05 (β, 0.80; 1-sided P value), we estimated that 7 patients per group were required. To allow for dropouts, we analyzed 15 patients per group.

Statistical Analysis

Data are presented as means ± SDs. Data were analyzed with 1-way analysis of variance, and distribution of residuals was investigated with the Shapiro-Wilk test. The Tukey post hoc analysis was performed with a confidence level of 99%; corresponding confidence intervals and P value were reported along with pairwise differences. A P value <0.01 was considered statistically significant.

RESULTS

Table 1 presents baseline characteristics of patients meeting criteria for inclusion in this study. No differences in sex, age, body mass index, rocuronium dose, and time to TOF2 were observed between groups. Table 2 presents surgical procedures followed by group. Table 3 reports the recovery time to TOF > 0.9 in seconds for each group. Recovery times to TOF > 0.9 for the dexamethasone after induction and the dexamethasone before reversal groups were not statistically different from the control group (P = 0.5141).

DISCUSSION

The aim of our study was to investigate the possible delay of neuromuscular function recovery in patients treated with sugammadex after rocuronium-induced neuromuscular relaxation and treated with dexamethasone for PONV prevention. Dexamethasone and rocuronium share the same cyclopenthanoperhydro-phenantrene structure, which is one of the determinants for sugammadex’s interaction. Because of this structure similarity, we hypothesized a potential competitive effect of dexamethasone on rocuronium binding to sugammadex, which could lead to delayed recovery of neuromuscular function. Our results did not confirm our hypothesis.

Previous work in vitro has suggested that dexamethasone may impair reversal of rocuronium neuromuscular blockade by sugammadex. Rezonja et al.5 studied the inhibition of sugammadex’s activity by dexamethasone on neuromuscular reversal in cultured human muscle cells. They used 10 μM rocuronium concentrations with 2 different sugammadex concentrations, 10 and 30 μM. The dexamethasone concentration ranged from nanomolar to micromolar with the maximal effect at 10 μM. They found that with sugammadex concentrations 3-fold larger than dexamethasone and rocuronium concentrations, dexamethasone exerted an inhibitory effect on sugammadex’s neuromuscular reversal. Although interesting, in vitro findings do not always translate to similar in vivo findings for several reasons. In vitro studies use a simple system compared with a human organism. In vivo cells are not in a static buffer, and extracellular drug concentrations are dependent on absorption, distribution, clearance, and protein binding.

Our results were not consistent with this previous work in vitro. One possible explanation is the difference in affinities of rocuronium and dexamethasone for sugammadex. Zwiers et al.4 determined in vitro association rate constants (kass) for 300 commonly prescribed drugs and sugammadex. They reported that the kass for rocuronium was 1.79 × 107 mol/L, whereas kass for dexamethasone was <1.00 × 103 mol/L, thus showing that rocuronium has a 10,000-fold greater affinity than dexamethasone for sugammadex binding. These findings suggest that the competitive effect of the corticosteroid on rocuronium binding with sugammadex is unlikely.

Previous work has measured peak plasma sugammadex concentrations of approximately 10 μM after a dosing scheme similar to the one used in our study.12 Although we did not measure rocuronium and dexamethasone plasma concentrations, they were likely less concentrated than sugammadex plasma concentrations based on the doses used and their respective pharmacokinetic characteristics.13,14 Nonetheless, it is important to point out that a proper comparison with previous finding in vitro is difficult, given that in vitro concentrations are likely more comparable with tissue concentrations rather than plasma concentrations.

Although not statistically significant, the time to recovery after sugammadex administration in the dexamethasone-treated groups tended to be shorter by 20 to 30 seconds (Table 3) than the control group, whose recovery time to TOF > 0.9 agrees with data reported in the literature for reversal of moderate rocuronium-induced neuromuscular block (TOF2) using 2 mg/kg sugammadex. The clinical implications of this trend are likely to be negligible. That being said, one possible explanation is that among dexamethasone’s multiple effects, it stabilizes neuromuscular junctions and facilitates neuromuscular transmission. Dalkara and Onur15 demonstrated an in vitro direct facilitatory action on neuromuscular transmission by a presynaptic action in mouse phrenic nerve-diaphragm preparation. Chen et al.16 demonstrated that chronic dexamethasone treatment induced an alteration in fiber composition in the rat diaphragm leading to desensitization to rocuronium. Soltész et al.17 evaluated the effect of a single 8-mg dexamethasone dose on rocuronium neuromuscular block, and they found that IV administration 2 to 3 hours before recovery makes the reversal of rocuronium-induced neuromuscular block 15% to 20% shorter.

Our study had several limitations. The TOF values were not normalized. Without normalization, the true TOF values may be longer than those reported, and variability may be more pronounced.18 To provide better stabilization, the TOF should have been calibrated using a tetanic stimulation to prevent the staircase phenomenon.19,20 Another limitation is that the control group should have consisted of patients treated with saline or no antiemetic drugs rather than ondansetron. Given the retrospective nature of our study and inclusion criteria of a risk of PONV, such a group of patients would have been impossible to find within our clinical records because they would have all been treated with prophylactic doses ondansetron or dexamethasone for PONV. This limitation may be of little consequence given that there are no in vitro or in vivo studies in the literature that have investigated a possible interaction between ondansetron and sugammadex. On the basis of the molecular structure of the 2 drugs, this interaction is very unlikely.

Although our results suggest that dexamethasone will not interfere with the reversal of rocuronium neuromuscular blockade with sugammadex, our findings may not be generalizable to all patients for several reasons. Patients in our analysis had a moderate neuromuscular block. No conclusions can be drawn about deep neuromuscular block, where sugammadex doses required for adequate reversal and subsequent plasma concentrations may be greater compared with moderate neuromuscular block. That being said, dosing of dexamethasone is likely to be the same regardless of the target neuromuscular blockade (moderate versus deep). Thus, it is unlikely that dexamethasone would inhibit sugammadex under these conditions.

In conclusion, our results show that prophylactic doses of dexamethasone for PONV prevention do not interfere with reversal of moderate neuromuscular blockade with sugammadex in contrast to previous studies in vitro.

Further studies on a larger population are required to confirm our findings. It also may be interesting to investigate the possible facilitatory action of dexamethasone on neuromuscular recovery in the clinical setting of sugammadex use for neuromuscular block reversal.